Medicines, by Dr. Enda O’Connell

In the ninth of our weekly series of articles, I have taken off my ReelLIFE SCIENCE hat and put on my Scientist hat.  Or labcoat, gloves and goggles, to be more precise…  As a Senior Technical Officer in NUI Galway, I support a range of research projects across the campus, from Cancer Biology and Stem Cell Research to Chemistry and Biomaterials.  In this article, I write about ‘Medicines’ and how researchers at NUI Galway are looking for new uses for old drugs.

The History of Medicines

Shennong3
Chinese Emperor Shennong tasting plants to test their qualities on himself (image from Wikipedia)

The word ‘medicine’ originally comes from the Latin phrase ‘ars medicina’, which translates as the ‘art of healing’, while the Oxford English Dictionary defines medicine (n) as ‘a substance or preparation used in the treatment of illness; a drug’. The earliest medicines were plant extracts, animal parts and minerals, and their use in healing rituals overseen by medicine men and shamans, often involved much more art than science. 

While many of the ‘cures’ recorded in ancient Egyptian texts had little or no effect on the intended ailment, some of the substances used have sound pharmacological reasons behind their effectiveness. Honey, used to treat wounds and burns, is a natural antiseptic, while willow extract, used to treat toothache, contains salicylic acid, the active ingredient in aspirin.  The Chinese Emperor Shennong is said to have personally tasted hundreds of herbs to test their medical (and poisonous) value, and his pharmacopoeia contains 365 medicines derived from animals, minerals and plants, including antimalarials, the herb Ephedra sinica (from which the stimulant ephedrine was eventually isolated) and tea.

Hippocrates - the 'Father of Medicine' (image from Wellcome Images)
Hippocrates – the ‘Father of Medicine’ (image from Wellcome Images)

Hippocrates, the “Father of Medicine”, lived in Greece between 460 and 370 BC, and is credited with applying a more logical, scientific approach to the diagnosis and treatment of various ailments, and writing the Hippocratic Oath requiring medical practitioners to uphold strict ethical standards when caring for patients. It is known that he would have had access to relatively pure forms of medicines such as opium (containing the painkiller morphine), iron sulphate (to treat anaemia) and zinc ore (zinc oxide is antibacterial and protects the skin against sun damage), which were all available in the ancient world.

In the Middle Ages, alchemy’s search for the ‘elixir of life’ gave way to the rational scientific discipline of medicinal chemistry, involving the purification of compounds such as arsenic (used to treat malaria, syphilis, ulcers and more) and mercury (used for skin disorders, syphilis and as a sedative).

Professor Sir Alexander Fleming, discoverer of Penicilling at his laboratory at St Mary's, Paddington, London. (image from Wikipedia)
Professor Alexander Fleming, discoverer of Penicillin, at his laboratory in London. (image from Wikipedia)

The 19th Century brought a further expansion of knowledge in the field, through the isolation of the active ingredients of medicinally beneficial plants, such as quinine (antimalarial), emetine (anti-parasitic and vomit inducer), cocaine (painkiller, stimulant, local anasthetic) and the aforementioned morphine, as well as the foundation of organic chemistry.  The 20th Century brought yet more developments including the discovery of vitamins, insulin, penicillin and various vaccines, chemotherapies and antiviral drugs, and the development of the pharmaceutical industry.

Current Trends in Medicines

Productivity of the Pharmaceutical Industry. The number of new drugs approved by the FDA per year has halved since 1996, while the cost of bringing a new drug to market has increased sixfold in that time (image credit  Akshat Rathi www.theconversation.com)
The number of new drugs approved each year by the FDA has halved since 1996, while the cost of bringing a new drug to market has increased sixfold in that time (image credit Akshat Rathi http://www.theconversation.com)

In all, 10,000 drugs are known to clinical medicine, with only 1,000 protected by patents, and the development of new drugs has declined rapidly in recent years. At the current approval rate it would take 300-400 years for the number of drugs in the world to double.  It is estimated that in 2013, the cost to pharmaceutical companies of bringing a new drug to market was a staggering $1.8 billion (although this may actually be as high as $5 billion), mainly due to the fact that 95% of compounds tested fail due to effectiveness or safety concerns.

It can take up to 15 years to develop a single drug, between: (i) discovering the drug (or often the drug target in the body); (ii) developing its chemical properties for manufacturing, stability and safety; (iii) pre-clinical trials (in vitro or animal models); (iv) clinical trials in human healthy volunteers to assess side effects; and finally (v) clinical trials in sick patients.

The Future of Medicines?

Aspirin_(2247084833)
40,000 tonnes of Aspirin are consumed worldwide each year (Photo by Chaval Brasil from Campinas, SP, Brasil (Flickr) [CC-BY-SA-2.0 (http://creativecommons.org/licenses/by-sa/2.0)%5D, via Wikimedia Commons)
 “The most fruitful basis for the discovery of a new drug is to start with an old drug.”  James Black, Nobel laureate and pharmacologist.

A recent trend has emerged where existing drugs are being ‘repurposed’ to treat other illnesses.  This has the benefit of greatly reducing the cost and time required finding a treatment, as much information about how the drug works, its safety and effectiveness in the body is generally known.  Drug repurposing is not new – many historical compounds such as zinc oxide and arsenic were recognised as having more than one use – but the increase in cost and decrease in productivity has driven the systematic re-examination of existing drugs as well as failed compounds which did not make it to market.

A well known example of repurposing is aspirin (salicylic acid), which has been used since ancient times to reduce pain and fever. In 1971 its mechanism of action was discovered by British pharmacologist John Robert Vane, for which he received the 1982 Nobel Prize in Physiology or Medicine.  This led to its antiplatelet (reduces blood clotting) function being described, and its long term, low dose prescription for those at risk of heart disease and strokes.  It is now used in huge quantities worldwide, with an estimated 40,000 tonnes consumed annually.

The Pfizer Active Pharmaceutical Ingredient Plant in Ringaskiddy, Cork where the drug Viagra is manufactured. (image from Pfizer website)
The Pfizer Active Pharmaceutical Ingredient Plant in Ringaskiddy, Cork where the drug Viagra is manufactured. (Image from Pfizer website)

Another often cited example of a drug finding a new lease of life is sildenafil citrate, more commonly known as Viagra.  Originally synthesised in 1989 by Pfizer scientists Andrew Bell, David Brown, and Nicholas Terrett in their search for a treatment for high blood pressure and angina, side effects observed during clinical trials led to it being widely used to treat erectile dysfunction.

An example of a repurposed failed compound (or rather a failed drug which was taken off the market due to catastrophic side effects) is the notorious sedative thalidomide.  Prescribed to pregnant women to alleviate morning sickness, it was withdrawn after an estimated 10,000 babies were born with malformed limbs, 50% of whom did not survive.  However, thalidomide is now used for the treatment of leprosy (US Food and Drug Administration (FDA) approved in 1998) and some cancers, e.g. multiple myeloma (FDA approved in 2006).

The Screening Core at NUI Galway

The NUI Galway Screening Core at Biosciences is a central resource for academic and industrial research groups looking to quickly expand and develop their current discovery research.
The NUI Galway Screening Core at Biosciences is a central resource for academic and industrial research groups looking to quickly expand and develop their current discovery research. The Perkin Elmer Janus system is an integral part of the Core’s infrastructure. (Image copyright NCBES, NUI Galway)

Researchers in NUI Galway are also looking for new ways to kill cancer cells.  While researching his PhD, Dr. David Monaghan, under the supervision of Dr. Howard Fearnhead (Pharmacology and Therapeutics lecturer and Principal Investigator in the Apoptosis Research Centre) focused on identifying existing drugs which may have an effect against drug resistant strains of breast cancer (the cancer cells literally pump out most chemotherapeutic drugs).

In my role managing the NUI Galway Screening Core at Biosciences, I was able to support David’s research by programming a robot we’ve christened ‘Janus’ (see the automated liquid handling workstation in the photo above) to greatly increase the number of drugs he could examine with his assay.  Over two weeks, we screened  the 1,500 FDA approved drugs in the Johns Hopkins Clinical Compound library for their ability to specifically kill these cancer cells. We recently published an article on one of the ‘hit’ compounds, the antiprotozoal drug anisomycin, which we’ve shown induces significant cell death in these drug resistant breast cancer cells.

Other researchers have since been supported by the Screening Core to screen this and other libraries against prostate and other forms of cancer, leading to the identification and characterisation of a number of potential chemotherapeutic drugs.  We also work with immunologists trying to improve healing after surgery, stem cell scientists, biomaterial scientists, chemists, biochemists and biomedical engineers.

To find out more about the NUI Galway Screening Core at Biosciences, visit http://ncbes.eurhost.net/screening-core-facility.aspx 

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